ReviewMECHANOMEDICINE

Targeting extracellular matrix stiffness to attenuate disease: From molecular mechanisms to clinical trials

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Science Translational Medicine  03 Jan 2018:
Vol. 10, Issue 422, eaao0475
DOI: 10.1126/scitranslmed.aao0475

Figures

  • Fig. 1 Putative mechanisms of ECM stiffening and cellular contractile forces generated in response to increased microenvironment stiffness.

    (A) Matrix cross-linking by lysyl oxidase (LOX), tissue transglutaminase (TG2), and advanced glycation end products (AGEs) in concert with increased matrix deposition are major contributors of pathological matrix stiffening. Inside-out and outside-in extracellular matrix (ECM) rigidity sensing is transmitted across cell adhesions composed of integrins and focal adhesion complexes. (B) Actomyosin cell contractility forces are increased in response to elevated matrix stiffness, and traction forces are exerted against the ECM. Cellular force is also propagated across the cell cytoplasm to the nucleus. (C) Stiffness-mediated traction forces transmitted across integrins cause a conformational change in the transforming growth factor β (TGFβ) latency complex to release TGFβ ligand and activate positive feedback cycles of ECM synthesis and stiffening. Solid blue arrows represent directionality of force transmission.

    CREDIT: A. KITTERMAN/SCIENCE TRANSLATIONAL MEDICINE
  • Fig. 2 Increased ECM stiffness activates the Rho-mediated cell contractility pathway.

    Mechanical force on integrins activates the Rho guanine nucleotide exchange factors (GEFs), GEF-H1 and LARG, to catalyze the exchange of guanosine diphosphate (GDP) for GTP. The major Rho effector Rho-associated kinase (ROCK) induces actomyosin cell contractility by phosphorylating myosin light chain phosphatase (MLCP) and myosin light chain (MLC). Downstream of Rho activation, myocardin-related transcription factor A (MRTF-A), yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), nuclear factor κB (NF-κB), and mitogen-activated protein kinase (MAPK) pathways regulate gene expression, and Rho activity has pathological implications on cell survival, migration, proliferation, and ECM synthesis. Solid arrows indicate direction of cellular traction force generation (blue) and Rho-mediated contractility pathway events (black). Dashed black arrows represent cellular responses downstream of Rho-mediated cell contractility.

    CREDIT: A. KITTERMAN/SCIENCE TRANSLATIONAL MEDICINE

Tables

  • Table 1 Therapeutics in latest clinical trials with primary end points specific to ECM stiffness.
    TargetDrug name
    (trade name/company)
    CategoryHighest
    completed trial
    Current trials relevant
    to ECM stiffness
    References
    miR-29MRG-201
    (miRagen Therapeutics Inc.)
    MicroRNAPhase 1None(26)
    NCT02603224
    CTGFFG-3019 (Fibrogen)Monoclonal antibodyPhase 2Phase 2(33, 34)
    NCT01890265
    NCT01262001
    TGFβ signalingPirfenidone
    (Esbriet/Genentech)
    Small molecule,
    mechanism unknown
    Approved:
    Idiopathic lung fibrosis
    Phase 1–3(36)
    NCT01872689
    NCT02552849
    NCT02408744
    NCT03068234
    NCT01872689
    TGFβGC1008
    (Fresolimumab/Genzyme)
    Monoclonal antibodyPhase 2Phase 1–2(37)
    NCT01401062
    NCT02581787
    NCT01665391
    VEGF, FGF, and
    PDGF receptors
    Nintedanib
    (Ofev/Boehringer Ingelheim)
    Small molecule, tyrosine
    kinase inhibitor
    Approved:
    Idiopathic lung fibrosis
    Phase 1–3NCT01284322
    LOXL2GS-6624
    (Simtuzumab/Gilead)
    Monoclonal antibodyPhase 2
    No efficacy in fibrosis
    or cancer
    None(5658)
    NCT01472198
    NCT01759511
    NCT 01769196
    LOXTetrathiomolybdateCopper chelatorPhase 3
    (Wilson’s disease)
    Phase 2(60)
    NCT00805805
    NCT00195091
    NCT01837329
    αvβ6BG00011/STX-100 (Biogen)Monoclonal antibodyPhase 2None(89)
    NCT01371305
    FAKVS-6063/PF-04554878
    (Defactinib/Verastem)
    Small moleculePhase 2Phase 1–2(117)
    NCT02943317
    NCT02758587
    NCT02546531
    NCT02465060
    FAKGSK-2256098
    (GlaxoSmithKline)
    Small moleculePhase 1Phase 1–2(117)
    NCT02551653
    NCT02428270
    NCT02523014
    NF-κBBortezomib
    (Velcade/Takeda)
    Small moleculeApproved:
    Multiple myeloma
    Phase 2(138, 139)
    NCT02370693
  • Table 2 Select FDA-approved drugs with repurposing potential for mechano-based therapeutic interventions.
    DrugTrade nameCompanyDiseaseTargetReference
    PirfenidoneEsbrietGenentechIdiopathic lung fibrosisTGFβ signaling(36)
    NintedanibOfevBoehringer IngelheimIdiopathic lung fibrosisVEGF, FGF,
    and PDGF receptors
    (40)
    StatinsMultipleMultipleCardiovascular diseaseRho, YAP/TAZ(98, 125)
    Verteporfin injectionVisudyneNovartisMacular degenerationYAP(126)
    BortezomibVelcadeTakedaMultiple myelomaNF-κB(138, 139)
    IxazomibNilaroTakedaMultiple myelomaNF-κB(139)
    CarfilzomibKyprolisAmgenMultiple myelomaNF-κB(138, 139)
    VemurafenibZelborafGenentechMelanomaB-Raf(146)
    DabrafenibTafinlarNovartisMelanomaB-Raf(145, 146)
    CobimetinibCotellicGenentechMelanomaMEK(146)
    TrametinibMekinistNovartisMelanomaMEK(145, 146)

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